Project Summary/Abstract A major challenge for treating drug addiction is the poor understanding of the molecular mechanisms by which drug use produces persistent changes in brain function that facilitate compulsive drug seeking and taking behaviors even after long periods of abstinence. We showed that MEF2 transcription factors regulate excitatory synapse density by promoting structural and functional synapse elimination in a process involving the Fragile X Mental Retardation Protein (FMRP) ? an RNA-binding protein that regulates dendritic protein synthesis and glutamatergic synaptic strength and density in the brain. FMRP acts to regulate multiple cocaine-induced behaviors and glutamatergic synapses on medium spiny neurons (MSNs) of the nucleus accumbens (NAc) shell. FMRP associates with hundreds of neuronal mRNAs, including the mRNA for the activity-regulated cytoskeleton-associated protein (Arc). In our preliminary studies, we find that Arc is induced in the NAc by cocaine and is a negative-regulator of NAc MSN glutamatergic synaptic transmission, and loss of Arc enables the development of sensitized cocaine bheaviors, including motor, reward and possibly sensitivity to low-dose cocaine in the mouse IV self-administration model. As such, our central hypothesis is that Arc RNA and protein synthesis in the NAc functions to antagonize glutamatergic synaptic plasticity on MSNs, and loss of Arc produces a synapse plasticity environment that facilitates sensitized cocaine behaviors. We will test and refine our central hypothesis with the following specific aims: Specific Aim 1: Analyze the regulation of Arc by cocaine in the adult NAc. In this aim, we will investigate the dynamic, cell-type specific regulation of Arc mRNA and protein in the adult NAc after acute and chronic cocaine (non-contingent and contingent) administration. Specific Aim 2: Determine the role of Arc in sensitized cocaine behaviors. In this aim, we will build upon our recent preliminary data to test for the role of Arc in the adult NAc for the development of non-contingent and contingent drug behaviors. Specific Aim 3: Determine the role of Arc in regulating cocaine-modulated NAc MSN excitatory synaptic transmission. Using a cell type-specific approach, we will investigate the role of Arc in mediating cocaine-induced (non-contingent and contingent) MSN glutamatergic synaptic strength and number with the hypothesis that Arc limits the sensitized cocaine behaviors by promoting AMPAR endocytosis of D1R+ MSNs in the adult NAc.